Organophosphorous compounds (OPs), due to their physical state and high lipophilicity, rapidly penetrate and accumulate in the central nervous system (CNS). OP poisoning of military personnel on the battlefield and of common citizens in the event of a terrorist attack with nerve gas, for example, has caused an increase in concern for public and governmental authorities around the world in recent years. In addition, increased demands for food and ornamental crops have resulted in an increase in the use of toxic anti-cholinesterase (anti-ChE)-based pesticides, including OPs such as parathion and malathion, in developed and developing countries. This has resulted in an increase in the accidental poisoning of farmers and gardeners.
It has long been known that the main toxic effects of OPs and other anti-ChE agents result from the inhibition of the enzyme ChE, which is responsible for the inactivation of the neurotransmitter acetylcholine (ACh) in the CNS and peripheral nervous system (PNS), thereby abnormally increasing and prolonging muscarinic and nicotinic cholinergic responses. Unfortunately, current methods to treat or prevent the toxic effects of OPs are still far from acceptable, particularly in the event of acute exposure to nerve agents that are highly absorbable and readily accessible to the brain.
Reversible ChE inhibitors, such as pyridostigmine bromine (PB), physostigmine, and huperzine, have been tested as antidotal therapy against OP poisoning. PB has been used as a preventive treatment by soldiers in the field. While it is a powerful anti-ChE agent, its action is mostly limited to the PNS, due to the fact that it is a charged molecule that hardly penetrates the CNS. Therefore, PB does not effectively confer protection of brain ChE against nerve gases. Physostigmine is more effective than PB, but less safe. Therefore, there currently is no method of protecting the brain from irreversible ChE inhibition by OPs. Rather, those individuals, who have been exposed to OP, have been treated post-exposure with antimuscarinic agents, such as atropine, ChE reactivators, such as oximes, e.g., pyridine-2-aldoxime (2-PAM), and anticonvulsants, e.g., Diazepam.
In view of the above, it is an object of the present invention to provide a method of treating OP poisoning. This and other objects and advantages, as well as additional inventive features, will become apparent from the detailed description provided herein.